An open‐label randomized study of the relative absorption of gastro‐resistant risedronate taken fasted or with food versus immediate‐release risedronate

Abstract Patients with osteoporosis often take oral bisphosphonates with food, rendering these medications ineffective. This study compared the relative absorption of four formulations of gastro‐resistant (GR; formulations 1–4) risedronate 35 mg versus immediate‐release (IR) risedronate 35 mg taken fasted. Secondarily, it compared the relative absorption of GR formulations administered fed and fasted, and determined the site of disintegration. Healthy participants (N = 160) were randomized to one of nine treatment groups: IR risedronate taken fasted (group A) or formulations 1–4 taken fasted or fed (groups B–I). Fasted groups fasted for 8 h pre‐dose and 4 h post‐dose. Fed groups fasted for 7.5 h, then took risedronate with breakfast. Urine was collected until 72 h post‐dose and analyzed using liquid chromatography. From each group, up to seven participants underwent scintigraphic monitoring to assess tablet disintegration. The percentage of total dose recovered in urine (A’e) was ~0.5% for group A. The A’e of formulations 1–4 taken fasted was 0.220% (90% confidence interval 0.124–0.389), 0.298% (0.122–0.730), 0.154% (0.090–0.264), and 0.108% (0.051–0.231), respectively. With food, the A’e of formulation 1 decreased least versus fasted (−27%) compared with the A’e of formulations 2, 3, and 4 (−73%, −80%, and −65%, respectively). Formulations 1–3 disintegrated in the small intestine, formulation 4 closer to the large intestine. All GR formulations were well tolerated and in line with the known safety profile for IR risedronate. Formulation 2 had the highest absorption when taken fasted, whereas the absorption of formulation 1 was least affected by food.


| INTRODUC TI ON
Osteoporosis is an age-related skeletal disease common in postmenopausal women and is characterized by decreasing bone mass and increased risk of fractures. 1,2 It affects approximately 20 million people in six of the largest countries in Europe, the majority of whom are female. 2 Oral bisphosphonates (BPs), such as risedronate, alendronate and ibandronate, are routinely recommended as first-line treatments for patients with osteoporosis. 1,3,4 In clinical trials, risedronate has demonstrated significant efficacy in reducing vertebral and non-vertebral fractures compared with placebo, 5,6 a finding that was further confirmed through real-world evidence. 7,8 When taken according to the dosage instructions, the absolute bioavailability of risedronate is <1% with oral administration. 9 If taken with food, the bioavailability of risedronate and other oral BPs is thought to be close to zero. [10][11][12] This may be because they form insoluble chelates with cations in food, such as calcium and magnesium. 10 Therefore, risedronate and other oral BPs must be taken on an empty stomach after an overnight fast with a ≥30-min wait before any food or drink. [13][14][15] In clinical practice, at least 30% of patients find it difficult to comply with the fasting instructions for oral BPs. 11,16 Recurrent non-compliance with fasting instructions means that patients may be more vulnerable to osteoporotic fractures. 17

| Study population
Healthy male and female participants were included if aged 40-70 years with a body mass index <32 kg m -2 . Female participants must have been non-lactating, and surgically sterile or postmenopausal (12 consecutive months without menses). All patients had to provide written informed consent. Participants were excluded if they had (1) any disease or surgery known to alter gastrointestinal (GI) structure or function; (2) a history of GI disease or GI surgery (apart from appendectomy and hernia repair that did not require bowel resection); (3) acute diarrhea or constipation (within 14 days prior to the predicted first study day); (4) a history of cancer within the past 5 years (apart from basal cell carcinoma with a 6-month remission or cervical carcinoma with a 12-month remission); (5) creatinine clearance (CrCl) of <60 ml min -1 ; (6) a history of substance abuse, a positive urine screen for drugs, or elevated alcohol consumption or tobacco use; (7) a known allergy to BPs or had used BPs within 6 months prior to dosing; (8)

| Study design
This was a randomized, open-label, single-dose, two-centre, parallel-group study. Participants were screened within 28 days before admission to the study site and assigned to one of nine treatment groups in equal numbers using block randomization (block size: 9; Table 1). Sample size was determined based on unpublished data 18 indicating that the percentage of the dose recovered in urine (A' e ) for the reference formulation was 0.40% with a percent coefficient of variation (CV%) of 100%. Assuming the CV% of the test formulations are also 100%, 15 subjects per treatment group provides 80% power for a one-sided t-test (α = 0. 10) to conclude that the A' e % of a test formulation is ≥45% of that of the reference formulation. This was an exploratory study. The primary objective was to compare the relative absorption of GR versus IR risedronate under fasted conditions. The secondary objectives were to compare the relative absorption of GR formulations when administered under fed and fasted conditions, as well as to determine the site of disintegration of GR tablets.  The actual lower limit of quantification of risedronic acid/ml of urine during study sample specimen analysis was 0.20 ng/ml of urine (0.216 ng/ml when corrected to risedronate sodium).

| Scintigraphic monitoring
A subset of up to seven participants per treatment group (males and surgically sterile females only) underwent scintigraphic monitoring to assess gastric emptying and tablet disintegration. Participants were excluded if they had participated in a study using radionuclides within the previous 3 months. The parameters assessed were: (1)

| Safety assessment
Safety was assessed through physical examination, vital signs, and adverse events (AEs) monitoring by the participants, the investigator or study site personnel. Suspected AEs were evaluated and appropriate treatment and follow-up provided as necessary. Participants with clinically significant AEs remained under medical supervision until the AE resolved, stabilized or was no longer serious enough to warrant follow-up (as assessed by the investigators).

| Statistical analysis
All statistical analyses were conducted using SAS ® Version 8 in the HP-UNIX environment or Microsoft ® Excel (Office 365 version 16.54). Continuous data (such as A e ) were summarized using descriptive statistics (e.g., mean, SD, median, minimum, maximum).
Categorical data (such as AEs) were summarized by treatment condition in counts and percentages. Nominal 90% confidence intervals

| Nomenclature of targets and ligands
Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guide topha rmaco logy.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Harding et al., 2018), 19 and are permanently archived in the Concise Guide to PHARMACOLOGY 2019/20 (Alexander et al., 2019). 20

| Patient characteristics
In total, 160 participants were randomized. Two subjects were withdrawn due to incomplete urine collection and 158 participants completed the study (Figure 1). Baseline characteristics were similar across treatment groups ( Table 2). Participants had a median age of 49.5 years with a median CrCl of 81.3 ml min -1 . The majority of participants were male and Caucasian.

| Pharmacokinetic results
The A e (in mg) was assessed over a 72-h period after dosing and expressed as A' e (%) ( Table 3 and Figure 2). This showed that ~0.5% of the dose was recovered in participants who received IR risedronate 35 mg.

| Scintigraphic results
Gastric emptying time, onset of disintegration and complete disintegration of GR tablets in the GI tract were assessed using scintigraphic monitoring ( Table 4). The mean gastric emptying time, time to initial disintegration and time to complete disintegration were all faster in the fasted state than in the fed state.
When examining the relationship between A e and site/time of disintegration, A e appears to be independent of the site of release prior to the ascending colon, after which it appears to decrease. In

| Safety
All GR formulations were well tolerated under fasted and fed conditions, with no serious AEs, discontinuation due to AE or deaths (Table 5). In total, 84 AEs were reported by 51 participants (mild severity: 65; moderate severity: 19). Of these, 49 AEs were possibly, and 4 AEs were probably, related to the study drug. There was no difference in the distribution, severity or causality of AEs according to GR formulation or whether participants received these in the fasted/fed state.

| DISCUSS ION
Oral BPs are a mainstay of treatment for osteoporosis, 1,3,4 with demonstrated effectiveness in reducing the incidence of fractures. [5][6][7][8] The bioavailability of oral BPs is low 9 and is further inhibited by food. [10][11][12] For this reason, patients may benefit from the availability of a GR formulation of oral BP that would allow them to take their medication with food. 21 The aim of this study was to assess the rela- Participants in this study received IR risedronate 35 mg after an overnight fast and 4 h before food. Analysis of A e after 72 h showed that the A' e was ~0.52% of the original 35 mg dose (Table 3). This is in line with previously published data showing that ~0.6% of the risedronate dose is absorbed when taken after an overnight fast and 4 h before food. 9 When taken according to the label instructions (30-min fast before food), the bioavailability of IR risedronate is reduced further. Indeed, Mitchell and colleagues reported that the amount of risedronate secreted in the urine was decreased by a further 55% when taken 30 min versus 4 h before food (indicated by the dashed line in Figure 2). 12 This effect was also confirmed by another study using 5 mg risedronate in a Japanese population. 22 Based on this, the A' e of formulation 2 taken in a fasted state (group B) is most similar to IR risedronate when taken according to the dosing instructions.
In Abbreviation: AE, adverse event. a AEs were defined as common if they occurred in >1% of the total participant population.
targeted release of risedronate in the small intestine, where it may be absorbed more readily than in the stomach.
In the fasted state, the mean A' e of risedronate GR formula- Limitations of this study included that the majority of participants were male (75%) and Caucasian (96%). Furthermore, the proportion of men and women differed between groups. Absorption is not expected to differ greatly in women, who are more likely than men to require BP therapy. Non-Caucasian populations (for example, Japanese) may have some differences in absorption, possibly related to diet, 22 but these are probably not clinically relevant. Also, this was a parallel group study, so some of the differences seen between treatments may be due to inter-group variability. The pooled urine sampling method, and the use of a single pharmacokinetic parameter (A' e ) as the primary variable, does not provide a detailed overview of the pharmacokinetics. In addition, A' e is a surrogate endpoint and represents only a small proportion of the ingested dose.
In conclusion, this study showed that risedronate GR formulation 2 (high 30% methacrylic acid copolymer type C coating, pH trigger 5.5) had the highest absorption when taken fasted, whereas the absorption of risedronate GR formulation 1 (low 10% methacrylic acid copolymer type C coating, pH trigger 5.5) was least affected by the presence of food (−27%).
Patients' adherence to their osteoporosis medication and compliance with dosing instructions are influenced by many factors, including convenience of the dosing regimen. 21,27 A GR formulation of risedronate 35 mg that could be taken with food would not only provide a more flexible dosing option to patients, but may also improve adherence and thus has the potential to be more effective in reducing fragility fractures. 4,17,21,28

ACK N OWLED G M ENTS
The authors thank Dr Stefanie Knappe and Nadine Leighton from

PR I N CI PA L I N V E S TI G ATO R S
The authors confirm that the Principal Investigators for this paper are Diane Kleinermans and Heather Wray and that they had direct clinical responsibility for healthy volunteers.

PATI E NT CO N S E NT
All participants provided written informed consent prior to the study.

CLI N I C A L TR I A L R EG I S TR ATI O N
This trial was conducted before 2013 and was not subject to mandatory registration. In addition, it did not include patients, but healthy volunteers.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from Theramex Ltd. Restrictions apply to the availability of these data, which were used under license for this study. Data are available from the authors with the permission of Theramex Ltd.